The invention relates to novel N-arylsulfonylamino acid omega-amides, processes for their preparation, and processes for their use as pharmaceuticals.
The publications EP 0 606 046, WO 95/35276 and WO 96/27583 describe arylsulfonaminohydroxamic acids and their action as matrix metalloproteinase inhibitors. Specific arylsulfonamidocarboxylic acids are used as intermediates for the preparation of thrombin inhibitors (EP 0 468 231) and aldose reductase inhibitors (EP 0 305 947). The publication EP 0 757 037 also describes the action of sulfonylamino acid derivatives as metalloproteinase inhibitors.
In the effort to find efficacious compounds for the treatment of connective tissue disorders, it has now been found that the sulfonylaminocarboxylic acids according to the invention are strong inhibitors of matrix metalloproteinases. Particular value is placed here on the inhibition of stromelysin (MMP-3) and neutrophil collagenase (MMP-8), as both enzymes are decisively involved in the degradation of the proteoglycans, as important constituents of the cartilaginous tissue (A. J. Fosang et al. J. Clin. Invest. 98 (1996) 2292-2299). Those enzymes which are involved in the constitutive degradation and synthesis of matrix constituents likewise belong to the protein family of the matrix metalloproteinases. For example, MMP-1 (collagenase xe2x80x941) has an important vital function, since it is involved in natural collagen degradation, in particular even where morphogenetic changes take place. Medicinal active compounds which, although they are able to inhibit MMP-3 and MMP-8, at the same time leave MMP-1 largely unaffected, are thus preferred. Such an active compound can even be particularly preferred with respect to the healing of the human or animal body, which, with, all in all, only moderate inhibition of MMP-3 and -8, shows no or a weaker effect on the MMP-1.
The invention therefore relates to the compound of the formula I: 
wherein,
R1 is selected from
1) unsubstituted phenyl,
2) phenyl monosubstituted or disubstituted with at least one substituent selected from linear (C1-C6)-alkyl, branched (C1-C6)-alkyl, cyclic(C3-C6)-alkyl, hydroxyl, (C1-C6)-alkyl-C(O)xe2x80x94Oxe2x80x94, (C1-C6)-alkyl-Oxe2x80x94, (C1-C6)-alkyl-Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94, halogen, CF3, CN, NO2, HOxe2x80x94C(O)xe2x80x94, (C1-C6)-alkyl-Oxe2x80x94C(O)xe2x80x94, methylenedioxo, R4xe2x80x94(R5) Nxe2x80x94C(O)xe2x80x94, and R4xe2x80x94(R5)Nxe2x80x94; substituted or unsubstituted isoxazolidine, morpholine, isothiazolidine, thiomorpholine, pyrazolidine, imidazolidine, piperazine, azetidine, pyrrole, pyrroline, pyrrolidine, pyridine, azepine, piperidine, oxazole, isoxazole, imidazole, pyrazole, thiazole, isothiazole, diazepine, thiomorpholine, pyrimidine, and pyrazine; and
3) a substituted or unsubstituted heteroaromatic group selected from pyrrole, pyrazole, imidazole, triazole, thiophene, thiazole, oxazole, isoxazole, pyridine, pyrimidine, indole, benzothiophene, benzimidazole, benzoxazole and benzothiazole;
R2 is selected from
1) hydrogen,
2) (C1-C6)-alkyl,
3) HOxe2x80x94C(O)xe2x80x94(C1-C6)-alkyl,
4) picolyl; and
5) phenyl-(CH2)nxe2x80x94, where phenyl is unsubstituted, or monosubstituted or disubstituted with at least one substituent selected from linear (C1-C6)-alkyl, branched (C1-C6)-alkyl, cyclic (C3-C6)-alkyl, hydroxyl, (C1-C6)-alkyl-C(O)xe2x80x94Oxe2x80x94, (C1-C6)-alkyl-Oxe2x80x94, (C1-C6)-alkyl-Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94, halogen, CF3, CN, NO2, HOxe2x80x94C(O)xe2x80x94, (C1-C6)-alkyl-Oxe2x80x94C(O), methylenedioxo, R4xe2x80x94(R5)NC(O), and R4xe2x80x94(R5)Nxe2x80x94;
n is selected from zero, 1, and 2;
R4 and R5 are independently selected from
1) hydrogen,
2) (C1-C6)-alkyl,
3) HOxe2x80x94C(O)xe2x80x94(C1-C6)-alkyl,
4) picolyl; and
5) phenyl-(CH2)nxe2x80x94, where phenyl is unsubstituted, monosubstituted, or disubstituted with at least one substituent selected from linear (C1-C6)-alkyl, branched (C1-C6)-alkyl, cyclic (C3-C6)-alkyl, hydroxyl, (C1-C6)-alkyl-C(O)xe2x80x94Oxe2x80x94, (C1-C6)-alkyl-Oxe2x80x94, (C1-C6)-alkyl-Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94, halogen, CF3, CN, NO2, HOxe2x80x94C(O)xe2x80x94, (C1-C6)-alkyl-Oxe2x80x94C(O), methylenedioxo, R4axe2x80x94(R5a)Nxe2x80x94C(O), and R4axe2x80x94(R5a)Nxe2x80x94; where R4a and R5a are independently selected from hydrogen, (C1-C6)-alkyl, HOxe2x80x94C(O)xe2x80x94(C1-C6)-alkyl, substituted or unsubstituted phenyl-(CH2)nxe2x80x94, and picolyl;
n is selected from zero, 1, and 2;
xe2x80x83or together R4 and R5, form a 4, 5, 6, or 7 membered ring with the nitrogen to which R4 and R5 are attached wherein at least one of the ring atoms is selected from
1) oxygen,
2) sulfur,
3) NH, and
4) carbon;
R3 is selected from
1) xe2x80x94(C1-C4)-alkyl-C(O)xe2x80x94N(R6)xe2x80x94R7,
2) xe2x80x94(C1-C4)-alkyl-C(O)xe2x80x94Y, and
3) xe2x80x94(C1-C4)-alkyl-C(O)xe2x80x94N(R9)xe2x80x94(CH2)Oxe2x80x94N(R4)xe2x80x94R5;
where R6 and R7 together with the nitrogen to which they are bonded form a radical selected from formulae IIa, IIb, and IIe: 
q is selected from zero, 1 and 2, and
r is selected from zero and 1,
Z is selected from
1) carbon,
2) nitrogen,
3) oxygen,
4) sulfur, and
5) a covalent bond;
R8 is selected from
1) hydrogen
2) linear (C1-C6)-alkyl,
3) branched (C1-C6)-alkyl,
4) cyclic (C3-C6)-alkyl,
5) hydroxyl,
6) (C1-C6)-alkyl-C(O)xe2x80x94Oxe2x80x94,
7) (C1-C6)-alkyl-Oxe2x80x94,
8) (C1-C6)-alkyl-Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94,
9) halogen,
10) CF3,
11) CN,
12) NO2,
13) HOxe2x80x94C(O)xe2x80x94,
14) (C1-C6)-alkyl-Oxe2x80x94C(O)xe2x80x94,
15) methylenedioxo,
16) R4xe2x80x94(R5)Nxe2x80x94C(O)xe2x80x94, and
17) R4xe2x80x94(R5)Nxe2x80x94,
o is selected from 2, 3, 4, and 5;
Y is selected from formulae IIc and IId: 
R9 is selected from
1) hydrogen,
2) (C1-C6)-alkyl-,
3) HOxe2x80x94C(O)xe2x80x94(C1-C6)-alkyl-,
4) picolyl,
5) phenyl-(CH2)nxe2x80x94, where phenyl is unsubstituted or monosubstituted or disubstituted with at least one substituent selected from linear (C1-C6)-alkyl, branched (C1-C6)-alkyl, cyclic (C3-C6)-alkyl, hydroxyl, (C1-C6)-alkyl-C(O)xe2x80x94Oxe2x80x94, (C1-C6)-alkyl-Oxe2x80x94, (C1-C6)-alkyl-Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94, halogen, CF3, CN, NO2,HOxe2x80x94C(O)xe2x80x94, (C1-C6)-alkyl-Oxe2x80x94C(O), methylenedioxo, R4xe2x80x94(R5)Nxe2x80x94C(O), and R4xe2x80x94(R5)Nxe2x80x94;
n is selected from zero, 1, and 2;
A is selected from a covalent bond, xe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, and xe2x80x94Cxe2x89xa1Cxe2x80x94;
B is selected from xe2x80x94(CH2)mxe2x80x94, xe2x80x94Oxe2x80x94(CH2)p, and xe2x80x94CHxe2x95x90CHxe2x80x94 where m is selected from zero, 1, 2, 3, 4, 5, and 6;
p is selected from 1, 2, 3, 4, and 5;
X is selected from xe2x80x94CHxe2x95x90CHxe2x80x94, oxygen and sulfur;
a stereoisomer or physiologically tolerable salt thereof.
In one embodiment, the invention provides for a compound of formula I, wherein
R1 is selected from
1) unsubstituted phenyl and
2) phenyl monosubstitued with a substituent selected from linear (C1-C6)-alkyl-, branched (C1-C6)-alkyl-, cyclic (C3-C6)-alkyl-, xe2x80x94OH, (C1-C6)-alkyl-C(O)xe2x80x94Oxe2x80x94, (C1-C6)-alkyl-Oxe2x80x94, (C1-C6)-alkyl-Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94, halogen, xe2x80x94CF3,or R4xe2x80x94(R5)Nxe2x80x94;
R2 is selected from hydrogen and (C1-C6)-alkyl;
R4 and R5 are independently selected from hydrogen and (C1-C6)-alkyl-, and
R4 and R5 together form a 4, 5, 6, or 7 membered ring with the nitrogen to which R4 and R5 are attached, wherein at least one of the ring atoms is selected from oxygen, sulfur, NH, and carbon;
R3 is selected from
1) xe2x80x94(C1-C4)-alkyl-C(O)xe2x80x94N(R6)xe2x80x94R7,
2) xe2x80x94(C1-C4)-alkyl-C(O)xe2x80x94Y, and
3) xe2x80x94(C1-C4)-alkyl-C(O)xe2x80x94N(R9)xe2x80x94(CH2)oxe2x80x94N(R4)xe2x80x94R5;
R6 and R7 together with the nitrogen to which they are bonded form a radical of formula IIa;
q is selected from zero and 1;
Z is selected from carbon, nitrogen, oxygen, and sulfur;
R8 is selected from hydrogen, linear (C1-C6)-alkyl, branched (C1-C6)-alkyl, cyclic (C3-C6)-alkyl hydroxyl, (C1-C6)-alkyl-C(O)xe2x80x94Oxe2x80x94, (C1-C6)-alkyl-Oxe2x80x94, (C1-C6)-alkyl-Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94, halogen, CF3, and CN;
R9 is a hydrogen atom;
o is selected from 2 and 3;
A is selected from a covalent bond and xe2x80x94Oxe2x80x94;
B is selected from (CH2)mxe2x80x94 and xe2x80x94Oxe2x80x94(CH2)p;
m is selected from 0, 1, and 2;
p is selected from 1 and 2; and
X is xe2x80x94CHxe2x95x90CHxe2x80x94.
In another embodiment of the invention, in the compound of formula I,
R1 is selected from
1) unsubstituted phenyl, and
2) phenyl monosubstituted with a substituent selected from chlorine, bromine, fluorine, pyrrolidine, and morpholine;
R2 is a hydrogen atom;
R3 is selected from
1) xe2x80x94(C1-C4)-alkyl-C(O)xe2x80x94N(R6)xe2x80x94R7,
2) xe2x80x94(C1-C4)-alkyl-C(O)xe2x80x94Y, and
3) xe2x80x94(C1-C4)-alkyl-C(O)xe2x80x94N(R9)xe2x80x94(CH2)oxe2x80x94N(R4)xe2x80x94R5;
q is selected from 0 and 1;
z is carbon;
R8 is selected from hydrogen, chlorine, bromine, and flourine;
R9 is hydrogen;
o is selected from 2 and 3;
R4 and R5 are independently selected from hydrogen, phenyl, and morpholine;
A is selected from a covalent bond and xe2x80x94Oxe2x80x94;
B is a covalent bond; and
X is xe2x80x94CHxe2x95x90CH.
The compounds 2-(biphenyl-4-sulfonylamino)4-(naphthalen-1-ylcarb-amoyl)butyric acid, 2-(biphenyl-4-sulfonylamino)-4-(naphthalen-2-yl-carbamoyl)butyric acid, 2-(biphenyl-4-sulfonylamino)-4-(2-phenylamino-ethylcarbamoyl)butyric acid, 2-(4xe2x80x2-chloro-biphenyl-4-sulfonylamino)-4-(3-morpholin-4-ylpropylcarbamoyl)butyric acid, 4-(3-(4-(biphenyl-4-sulfonyl-amino)4-carboxybutyrylamino)propyl)morpholin-4-ium trifluoroacetate, 2-(biphenyl-4-sulfonylamino)-5-(2,3-dihydroindol-1-yl)-5-oxopentanoic acid, 5-(2,3-dihydroindol-1-yl)-5-oxo-2-(4xe2x80x2-pyrrolidin-1-yl-biphenyl-4-sulfonyl-amino)pentanoic acid, 2-(4xe2x80x2-chlorobiphenyl-4-sulfonylamino)-5-(2,3-dihydroindol-1-yl)-5-oxopentanoic acid, 2-(4xe2x80x2-bromobiphenyl-4-sulfonyl-amino)-5-(2,3-dihydroindol-1-yl)-5-oxopentanoic acid, 2-(4xe2x80x2-chloro-biphenyl-4-sulfonylamino)-5-(5-fluoro-2,3-dihydroindol-1-yl)-5-oxopentanoic acid, 2-(4xe2x80x2-bromobiphenyl-4-sulfonylamino)-5-(5-fluoro-2,3-dihydroindol-1-yl)-5-ox-opentanoic acid, 5-(5-fluoro-2,3-dihydroindol-1-yl)-5-oxo-2-(4xe2x80x2-pyrrolidin-1-ylbiphenyl-4-sulfonylamino)pentanoic acid and 5-(5-fluoro-2,3-dihydroindol-1-yl)-2-(4xe2x80x2-morpholin-4-yl-biphenyl-4-sulfonylamino)-5-oxopentanoic acid are currently particularly preferred.
It is understood that the heterocycle substituents of R1; which include isoxazolidine, morpholine, isothiazolidine, thiomorpholine, pyrazolidine, imidazolidine, piperazine, azetidine, pyrrole, pyrroline, pyrrolidine, pyridine, azepine, piperidine, oxazole, isoxazole, imidazole, pyrazole, thiazole, isothiazole, diazepine, thiomorpholine, pyrimidine, and pyrazine; may be substituted with at least one substituent selected from linear (C1-C6)-alkyl, branched (C1-C6)-alkyl, cyclic (C3-C6)-alkyl, hydroxyl, (C1-C6)-alkyl-C(O)xe2x80x94Oxe2x80x94, (C1-C6)-alkyl-Oxe2x80x94, (C1-C6)-alkyl-Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94, halogen, CF3, CN, NO2, HOxe2x80x94C(O)xe2x80x94, (C1-C6)-alkyl-Oxe2x80x94C(O)xe2x80x94, methylenedioxo, R4xe2x80x94(R5) Nxe2x80x94C(O)xe2x80x94, and R4xe2x80x94(R5)Nxe2x80x94.
It is also understood that the heteroaromatic group substituents of R1; which include pyrrole, pyrazole, imidazole, triazole, thiophene, thiazole, oxazole, isoxazole, pyridine, pyrimidine, indole, benzothiophene, benzimidazole, benzoxazole and benzothiazole; may be substituted with at least one substituent selected from linear (C1-C6)-alkyl, branched (C1-C6)-alkyl, cyclic (C3-C6)-alkyl, hydroxyl, (C1-C6)-alkyl-C(O)xe2x80x94Oxe2x80x94, (C1-C6)-alkyl-Oxe2x80x94, (C1-C6)-alkyl-Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94, halogen, CF3, CN, NO2, HOxe2x80x94C(O)xe2x80x94, (C1-C6)-alkyl-Oxe2x80x94C(O)xe2x80x94, methylenedioxo, R4xe2x80x94(R5) Nxe2x80x94C(O)xe2x80x94, and R4xe2x80x94(R5)Nxe2x80x94.
It is further understood that a substituted phenyl includes, but is not limited to, the following substituents: linear (C1-C6)-alkyl, branched (C1-C6)-alkyl, cyclic (C3-C6)-alkyl, hydroxyl, (C1-C6)-alkyl-C(O)xe2x80x94Oxe2x80x94, (C1-C6)-alkyl-Oxe2x80x94, (C1-C6)-alkyl-Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94, halogen, CF3, CN, NO2, HOxe2x80x94C(O)xe2x80x94, (C1-C6)-alkyl-Oxe2x80x94C(O), and methylenedioxo.
When R4 and R5 together form a 4, 5, 6, or 7 membered ring with the nitrogen to which R4 and R5 are attached wherein at least one of the ring atoms is selected from oxygen, sulfur, NH, and carbon, it is understood that that ring may be derived from compounds including isoxazolidine, morpholine, isothiazolidine, thiomorpholine, pyrazolidine, imidazolidine, piperazine, azetidine, pyrrole, pyrroline, pyrrolidine, pyridine, azepine, piperidine, pyrazole and diazepine.
The term xe2x80x9chalogenxe2x80x9d is understood as meaning fluorine, chlorine, bromine or iodine.
The term xe2x80x9calkylxe2x80x9d is understood as meaning hydrocarbon radicals whose carbon chain is linear or branched.
The starting substances of the chemical reactions are known or can easily be prepared by methods known from the literature.
The invention furthermore relates to processes for the preparation of the compound of the formula I, a stereoisomeric form thereof, and a physiologically tolerable salt thereof.
In one process, a compound of formula I is prepared by a) reacting an aminocarboxylic acid of the formula II: 
R11 is selected from hydrogen and an ester protecting group;
s is selected from zero, 1, 2 and 3;
R10 is selected from xe2x80x94OR12, a hydrogen atom, and xe2x80x94N(R6)xe2x80x94R7,
R12 is an ester protecting group;
with a sulfonic acid derivative of the formula III: 
wherein
Y is selected from
1) halogen,
2) imidazolyl, and
3) OR13;
R13 is selected from substituted or unsubstituted (C1-C6)-alkyl, substituted or unsubstituted (C1-C6)-phenyl, and substituted or unsubstituted (C1-C6)-benzyl;
in the presence of a base or, if appropriate, of a dehydrating agent to give a compound of the formula IV: 
by removing the protecting group R12 and by introducing xe2x80x94N(R6)xe2x80x94R7 by known peptide chemistry techniques, followed by removal of R11, one may form a compound of formula I.
In another preferred embodiment, a compound of formula I can be prepared by a process comprising:
a) reacting an amino acid anhydride of the formula V: 
wherein,
R13 is hydrogen;
R14 is an N-protecting group which includes carbobenzyloxy (Z); or together R13 and R14 are a cyclic N-protecting group such as phthalimido,
with a primary or secondary radical xe2x80x94N(R6)xe2x80x94R7 to open the anhydride ring to give an intermediate of the formula VI: 
This ring opening, depending on the protecting group and reaction conditions (cf., X. Huang, X. Luo, Y. Roupioz, J. W. Keillor, J. Org. Chem. 1997, 62, 8821-8825) as a rule regioselectively yields the isomer shown in formula VI, which, if regioisomer mixtures occur, can be further enriched by crystallization or chromatography. Cleaving the included protecting group (R13, R14 or both) with the release of the amine, followed by an N-sulfonation with a sulfonic acid derivative of the formula III as previously described leads to a product of the formula I.
In another embodiment of the invention, resolving a compound of the formula I prepared according to the processes of the invention which, on account of its chemical structure, occurs in enantiomeric forms may be accomplished. The resolution into the pure enantiomers may be performed by salt formation with enantiomerically pure acids or bases, chromatography on chiral stationary phases, or derivatization by means of chiral enantiomerically pure compounds such as amino acids. Separation of the diastereomers is thereby obtained. Removal of the chiral auxiliary groups, or isolating the compound of the formula I prepared according to the processes of the invention in free form or, if acidic or basic groups are present, converting it into physiologically tolerable salts may then be performed.
Suitable protecting groups for this are preferably the customary N-protecting groups used in peptide chemistry, for example protecting groups of the urethane type, benzyloxycarbonyl (Z), t-butyloxycarbonyl (Boc), 9-fluorenyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc) or of the acid amide type, in particular formyl, acetyl or trifluoroacetyl, and of the alkyl type, for example benzyl.
Starting materials used for the preparation of the sulfonic acid derivatives of the formula III are preferably sulfonic acids or their salts of the formula VII, for example 
where R15 has the same meaning as R1.
Sulfonic acid derivatives of the formula II, which like R15 contain a secondary or cyclic amine of the type xe2x80x94N(R4)xe2x80x94R5, are prepared preferably and in high yields by Pd-catalyzed substitution of a bisaryl halide, preferably of a bromide, by a secondary amine following known literature procedures (cf. A. S. Guram, R. A. Rennels, S. L. Buchwald; Angew. Chem. 1995, 107, 1456-1459) and subsequent sulfochlorination by means of chlorosulfonic acid. The sulfochloride function is in this case preferably guided into the desired para position by the directing effect of the amine group.
The catalyst dichlorobis(tritolylphosphine)palladium(II) advantageously used can be prepared analogously to R. F. Heck in xe2x80x9cPalladium Reagents in Organic Synthesesxe2x80x9d, Academic Press, London (1985), p. 18 starting from tri-o-tolylphosphine, palladium(II) chloride and LiCl in methanol.
For the preparation of the arylsulfonic acids of the formulae VIIa and VIIb, the sulfonation process with concentrated sulfuric acid described in Houben-Weyl xe2x80x9cMethoden der Organischen Chemiexe2x80x9d [Methods of Organic Chemistry] volume 9, pp. 540-546 is preferably used, if appropriate in the presence of a catalyst, sulfur trioxide and its addition compounds or halosulfonic acids, such as chlorosulfonic acid. Particularly in the case of the diphenyl ethers of the formula VIIb, the use of concentrated sulfuric acid and acetic anhydride as a solvent (cf., C. M. Suter, J. Am. Chem. Soc. 53 (1931) 1114), or the reaction with excess chlorosulfonic acid (J. P. Bassin, R. Cremlyn and F. Swinbourne; Phosphorus, Sulfur and Silicon 72 (1992) 157) has proven suitable. Sulfonic acids according to the formulae VIIc, VIId, or VIIe can be prepared in a manner known per se by reacting the appropriate arylalkyl halide with sulfites such as sodium sulfite or ammonium sulfite in aqueous or aqueous/alcoholic solution, it being possible to accelerate the reaction in the presence of tetraorganoammonium salts such as tetrabutylammonium chloride.
Sulfonic acid derivatives according to formula III used, are, in particular, the sulfonyl chlorides. For their preparation, the corresponding sulfonic acids, also in the form of their salts such as sodium, ammonium or pyridinium salts, are reacted in a known manner with phosphorus pentachloride or thionyl chloride without or in the presence of a solvent such as phosphorus oxychloride or of an inert solvent such as methylene chloride, cyclohexane or chloroform, in general at reaction temperatures of 20xc2x0 C. up to the boiling point of the reaction medium used. Advantageously, the direct sulfochlorination of the appropriate aromatic can also be carried out using chlorosulfonic acid, sulfuryl chloride or pyrosulfuryl chloride (Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], volume 9 (1995), pages 572-579).
The reaction of the sulfonic acid derivatives of the formula III with the amino acids of the formula II according to process according to the invention proceeds advantageously in the style of the Schotten-Baumann reaction. Suitable bases for this are particularly alkali metal hydroxides such as sodium hydroxide, but also alkali metal acetates, alkali metal hydrogencarbonates, alkali metal carbonates and amines. The reaction takes place in water or in a water-miscible or nonmiscible solvent such as tetrahydrofuran (THF), acetone, dioxane or acetonitrile, the reaction temperature in general being kept from xe2x88x9210xc2x0 C. to 50xc2x0 C. In the case in which the reaction is carried out in anhydrous medium, tetrahydrofuran or methylene chloride, acetonitrile or dioxane in the presence of a base, such as triethylamine, N-methylmorpholine, N-ethyl- or diisopropylethylamine is especially used, optionally in the presence of N,N-dimethylaminopyridine as a catalyst.
In another variant, particularly when using polar starting materials which are present in unprotected form, the aminocarboxylic acids of the formula II can first be converted into their silylated form with the aid of a silylating agent such as bis-trimethylsilyl trifluoroacetamide (BSTFA) and they then react with sulfonic acid derivatives to give compounds of the formula IV.
The physiologically tolerable salts of the compounds of the formula I capable of salt formation, including their stereoisomeric forms, are readily prepared. With basic reagents such as hydroxides, carbonates, hydrogencarbonates, alkoxides and ammonia or organic bases, for example 2-amino-2-hydroxymethyl-1,3-propanediol (tromethamine), trimethyl- or triethylamine, ethanolamine or triethanolamine or alternatively basic amino acids, for example lysine, ornithine or arginine, the carboxylic acids form stable alkali metal, alkaline earth metal or, if appropriate, substituted ammonium salts. Salts of the compound of the formula I which are formed with the organic bases mentioned show a high water solubility. If the compounds of the formula I have basic groups, stable acid addition salts can also be prepared using strong acids. For this, both inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, 4-bromobenzenesulfonic, acetic, oxalic, tartaric, trifluoromethylsulfonic, cyclohexylamidosulfonic, succinic or trifluoroacetic acid are suitable.
The invention also relates to pharmaceuticals which contain an efficacious amount of at least one compound of the formula I, a physiologically tolerable salt thereof, and an optionally stereoisomeric form thereof, together with a pharmaceutically suitable and physiologically tolerable excipient, additive or other active compounds and auxiliaries.
On account of their pharmacological properties, the compounds according to the invention are suitable for the prophylaxis and therapy of all those disorders in whose course matrix-degrading metalloproteinases are involved. These include degenerative joint disorders such as osteoarthroses, rheumatoid arthritis, spondyloses, chondrolysis after joint trauma or relatively long immobilization of the joint, e.g. after meniscus or patella injuries or tearing of the ligaments. In addition, these also include disorders of the connective tissue such as collagenoses, periodontal disorders, which can even lead to the loss of the teeth, wound healing disorders and chronic disorders of the locomotory apparatus such as inflammatory, immunologically, or metabolically caused acute and chronic arthritis, arthropathies, myalgias, and disorders of the bone metabolism (such as osteoporosis). The medicinal use of the compounds of the formula I according to the invention may be indicated in the case of vascular diseases, e.g. blood vessel occlusions, atherosclerotic plaques or aneurysms, particularly in threatening rupture, or in stenoses of any pathogenesis. The compounds of the formula I are furthermore suitable for the treatment of inflammations, including wounds and ulcers, in particular also those of the skin, carcinomatous disorders, in particular also for blocking or checking the formation and spread of metastases, and also in carcinoma of the breast. Cachexia, anorexia, and septic shock and also periodontosis and periodontitis are further medicinal areas of application for the compounds according to the invention.
In general, the pharmaceuticals according to the invention are administered orally or parenterally. Rectal or transdermal administration is also possible.
The invention also relates to a process for the production of a pharmaceutical, which comprises bringing at least one compound of the formula I into a suitable administration form using a pharmaceutically suitable and physiologically tolerable vehicle, and, if appropriate, further suitable active compounds, additives or auxiliaries.
Suitable solid or pharmaceutical preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions as well as preparations with protracted release of active compound, in whose preparation customary auxiliaries, such as excipients, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers are used. Frequently used auxiliaries which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod-liver oil, sunflower oil, peanut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.
The pharmaceutical preparations are preferably prepared and administered in dose units, each unit containing as active constituent a specific dose of the compound of the formula I according to the invention. In the case of solid dose units such as tablets, capsules, coated tablets or suppositories, this dose can be up to approximately 1000 mg, but preferably approximately 50 to 300 mg and, in the case of injection solutions in ampoule form, up to approximately 300 mg, but preferably approximately 10 to 100 mg.
For the treatment of an adult patient weighing approximately 70 kg, depending on the efficacy of the compounds according to formula I, daily doses of approximately 20 mg to 1000 mg of active compound, preferably approximately 100 mg to 500 mg, are indicated. Under certain circumstances, however, even higher or lower daily doses may be appropriate. The daily dose can be administered both by single administration in the form of an individual dose unit or else of several smaller dose units and by multiple administration of subdivided doses at intervals.
The compounds on which the invention is based were identified by nuclear magnetic resonance and mass spectroscopy, where in the case of the presence of regio- or diastereoisomeric forms in addition to 1H also 13C and multidimensional NMR methods were employed for clear proof of structure. 1H NMR spectra have been recorded on a 400 MHz apparatus from Bruker, as a rule using tetramethylsilane (TMS) as an internal standard and at room temperature (RT). As a rule, final products are determined by mass spectroscopic methods (FAB-, ESI-MS with positive or negative ionization). Temperatures are in degrees Celsius, RT means room temperature (22xc2x0 C. to 26xc2x0 C.). Abbreviations used are either explained or correspond to the customary conventions.